title: The disintegrin eristostatin interferes with integrin alpha 4 beta 1 function and with experimental metastasis of human melanoma cells.
abstract: Peptides containing the integrin recognition sequence, RGD, can inhibit experimental metastasis of mouse melanoma cells, but the integrin(s) affected in these experiments is unknown. Besides "classical" RGD-binding integrins such as alpha 5 beta 1 and alpha v beta 3, RGD has been reported to bind alpha 4 beta 1, and mAbs to alpha 4 beta 1 can inhibit melanoma metastasis. We investigated the mode of action of the disintegrin eristostatin, an RGD-containing peptide isolated from snake venom, in a human melanoma experimental metastasis model. Lung colonization following i.v. injection of MV3 cells in nude mice was strongly inhibited by eristostatin. MV3 cells bound FITC-eristostatin and adhered to eristostatin-coated wells. This adhesion was partially inhibited by a GRGDSP peptide and by alpha 4 mAb. Binding of FITC-eristostatin to Jurkat cells and adhesion of Jurkat (but not K562) cells to eristostatin-coated wells further suggested that eristostatin binds alpha 4 beta 1, even though, again, alpha 4 mAb only partially inhibited adhesion. Expression of alpha 4 beta 1 was enhanced in metastatic melanoma cells compared to normal melanocytes and nonmetastatic melanoma cells. Finally, eristostatin inhibited adhesion of both MV3 and CHO alpha 4 cells to the alpha 4 beta 1-ligand VCAM-1, while adhesion to other ligands via other integrins was not affected. These findings demonstrate that inhibition of melanoma cell metastasis by RGD-containing peptides such as eristostatin, may be due to interference with alpha 4 beta 1-VCAM binding, in addition to inhibition of the classical RGD-binding integrins.
authors.affiliation: Department of Pathology, University Hospital, Nijmegen, The Netherlands. edanen@yoda.nidr.nih.gov
authors.forename: E H
authors.initials: EH
authors.lastname: Danen
authors.forename: C
authors.initials: C
authors.lastname: Marcinkiewicz
authors.forename: I M
authors.initials: IM
authors.lastname: Cornelissen
authors.forename: A A
authors.initials: AA
authors.lastname: van Kraats
authors.forename: J A
authors.initials: JA
authors.lastname: Pachter
authors.forename: D J
authors.initials: DJ
authors.lastname: Ruiter
authors.forename: S
authors.initials: S
authors.lastname: Niewiarowski
authors.forename: G N
authors.initials: GN
authors.lastname: van Muijen
mesh_terms: D000818:Animals; D001665:Binding Sites; D006801:Humans; D007231:Infant, Newborn; D039041:Integrin alpha4beta1; D016023:Integrins / Q000737:chemistry / Q000187:drug effects / Q000502:physiology*; D036341:Intercellular Signaling Peptides and Proteins; D008297:Male; D008544:Melanocytes / Q000166:cytology; D008545:Melanoma / Q000188:drug therapy / Q000473:pathology* / Q000503:physiopathology; D051379:Mice; D008819:Mice, Nude; D009362:Neoplasm Metastasis / Q000517:prevention & control; D009842:Oligopeptides; D010455:Peptides / Q000493:pharmacokinetics / Q000627:therapeutic use*; D010975:Platelet Aggregation Inhibitors / Q000627:therapeutic use; D016201:Receptors, Lymphocyte Homing / Q000737:chemistry / Q000187:drug effects / Q000502:physiology*; D012867:Skin / Q000166:cytology; D012878:Skin Neoplasms / Q000188:drug therapy / Q000473:pathology* / Q000503:physiopathology; D012910:Snake Venoms; D014757:Viper Venoms / Q000493:pharmacokinetics / Q000627:therapeutic use*
chemical_list: D039041:Integrin alpha4beta1; D016023:Integrins; D036341:Intercellular Signaling Peptides and Proteins; D009842:Oligopeptides; D010455:Peptides; D010975:Platelet Aggregation Inhibitors; D016201:Receptors, Lymphocyte Homing; D012910:Snake Venoms; D014757:Viper Venoms; C057986:echistatin; C062186:bitistatin; C084060:eristostatin; C047981:arginyl-glycyl-aspartic acid